The modern drug discovery process often starts with identification of a compound which shows activities toward a biological target for a disease process; such a compound may be called a drug lead. The biological target may include, for example: a protein, a peptide, a nucleotide, a nucleic acid, a carbohydrate, an assembly of the above, a membrane, a cell, and/or a tissue. It is often necessary to improve a drug lead compound. Such improvement may be designed to, for example, make the drug lead have a high affinity or increased activity toward the biological target. The improvement may also be designed to improve the metabolic stability of the drug lead, improve the cell membrane permeability of the drug lead, etc. before the drug lead is generally selected as candidate for further development. In the process of improving the properties of the drug lead, a number of modified structures of the drug lead compound may first be designed. More specifically, the modified structures of the drug lead may be based on known mechanism of action of the drug lead and the structural information of the biological target. Alternatively, the modified structures of the drug lead may be based on chemical and/or biological intuitions, such as when the structure of the biological target or the mode of action of the drug lead is not precisely known. Next, the designed compounds may be synthesized, purified and tested individually for their properties. This process may be carried out several times before a modified drug lead having satisfying properties is discovered and selected for further development. Current methods of modifying a drug lead structure may be based on organic synthesis reactions with a primary goal of producing a desired single synthetic product having a high yield. (Nogrady, T. and Weaver, D. F., Medicinal chemistry: a molecular and biochemical approach, Oxford University Press, 2005; Thomas, G., Fundamentals of medicinal chemistry, Wiley, New York, 2003; Corey, E. J. and Cheng, X.-M., The Logic of Chemical Synthesis, Wiley, New York, 1989).
Often, the design of the structural modification is limited to known organic reactions at structural positions that may produce the desired single product in high yield. Accordingly, highly selective reactions are preferred for synthesizing the desired compound, one at a time. FIG. 1 of the present method illustrates such a process using a common drug, ibuprofen (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid) as an example of a drug lead. For a given drug lead compound, often there are only a few structural positions available for traditional modifications, as shown in FIG. 1. Methods are also available for making more than one structural modifications in the same reaction. A split synthesis technique may be implemented to make multiple products in a single reaction step. This technique has been used in drug discovery research. (Nikolai F. Sepetov, et al. U.S. Pat. No. 6,799,120—Nonredundant split/pool synthesis of combinatorial libraries, US Patent Issued on Sep. 28, 2004; Lam, K. S., et al. “The ‘one-bead-one-compound’ combinatorial library method,” Chem. Rev. 1997, 97, 411-448; Furka, A. and Bennett, W. D. “Combinatorial libraries by portioning and mixing,” Comb. Chem. High Throughput Screening 1999, 2, 105-122). In the split synthesis process multiple parallel reactions are carried out, desired single product of each reaction are purified and are mixed together in the next reaction step to produce multiple products. This split synthesis method is illustrated in FIG. 2 again using ibuprofen as an example. Although the split synthesis technique can make multiple products in a single reaction step, the technique has the limitation that the modification is done only at structural positions where each of the multiple starting materials can produce the desired single product in high yield. Methods that can make modifications of a drug lead structure at more structural positions will produce products covering more structural space. That type of drug lead modification products will allow more fully examination of the effect of structural modification of a drug lead and will provide greater probability of finding modified structures with improved drug properties. Thus, there exists a need for methods that can more fully modify a drug lead structure for the discovery of compounds with improved drug properties. The present method satisfies this need and provides related advantages as well.